Disease/Drug of Interest: cUTI / gentamicin Motivation and Background: Urinary tract infections (UTIs) are a type of infection caused by bacteria that travel to the bladder through the urethra. A bladder infection is called cystitis. An infection that has spread to the kidneys and ureters is called pyelonephritis. Cystitis is considered a lower urinary tract infection, whereas pyelonephritis is an upper urinary tract infection [1]. UTIs are extremely common bacterial infections, and they can occur at any time in the life of an individual. Women are especially prone to UTIs because they have shorter urethras. It is estimated that one in every five women will have at least one UTI in her lifetime. The chances of a man getting a UTI are significantly lower [2]. In addition to there being lower and upper urinary tract infections, there are also uncomplicated and complicated infections. An uncomplicated UTI is defined as being cystitis or pyelonephritis in a woman who is not pregnant, is not immunocompromised, has no anatomical or functional abnormalities of the urogenital tract, and does not exhibit signs of tissue invasion or systemic infection. All other UTIs are considered to be complicated infections (cUTIs) [3]. Symptoms of both uncomplicated and complicated UTIs include the following: a burning sensation during urination, fever or chills, an intense and constant urge to urinate, discomfort around the kidneys, cloudy or bloody urine, and intense fatigue. Escherichia coli is associated with around 90% of all urinary tract infections, both uncomplicated and complicated [4]. E. coli CFT073 is a common strain found in many cases of uncomplicated and complicated UTIs. In order to fight complicated infections, gentamicin is often used in combination with another antibiotic. Because UTIs affect so many women and are one of the most common bacterial infections in the United States, it would be well worth the investment to fund research to find more effective preventative and treatment options for the infection. Target Information: A prokaryotic ribosome is a cytoplasmic particle composed of RNA and protein. Ribosomes are built of two subunits that associate for mRNA translation and protein synthesis. 30S is the smaller subunit of the 70S ribosome found in prokaryotes. It complexes with the larger 50S subunit to form the 70S prokaryotic ribosome. The RNA chain found in the 30S subunit is the 16S ribosomal RNA sequence. Size: The 50S subunit has a molecular weight of ∼1.5 × 106 Daltons and contains two RNA chains with a total of ∼3000 nucleotides and ∼35 proteins. The 30S subunit has a molecular weight of ∼8.5 × 105 Daltons and contains one RNA chain of over 1500 nucleotides and ∼20 proteins. Location: Because prokaryotes contain no membrane-bound organelles, ribosomal subunits are always found in the cytosol. Function in a Normal Cell: The main function of a prokaryotic ribosome is to serve as the site of mRNA translation and protein synthesis. In a normal bacterial cell, initiation of translation, elongation, and termination occur properly and work to produce functional proteins. The initiation stage of translation brings together mRNA, an aminoacyl tRNA, and the 50S and 30S subunits. In the elongation stage of translation, amino acids are added to the previous amino acid at the C-terminus of the growing chain. The final stage of translation is termination. Figure 1: 30S subunit without the 16S rRNA from http://www.biochem.umd.edu/biochem/kahn/bchm465-01/ribosome/30s.html Figure 2: 30S subunit with the 16S rRNA from http://www.biochem.umd.edu/biochem/kahn/bchm465-01/ribosome/30s.html Drug Information: Aminoglycosides primarily act by binding to the aminoacyl site of the 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation. The initial steps required for proper translation, such as the binding of mRNA and the association of the 50S ribosomal subunit, are uninterrupted, but elongation fails to occur properly due to disruption of the mechanisms for ensuring translational accuracy [6]. By interrupting elongation, aminoglycosides cause the prokaryotic cell to produce non-functional proteins. The bacterial cell will be unable to carry out necessary cellular functions if it continues to produce non-functional proteins; therefore, the cell will eventually die. Gentamicin is the most commonly used aminoglycoside for cUTIs. Schematic Figure of Drug: Figure 3: Gentamicin from https://pubchem.ncbi.nlm.nih.gov/compound/gentamicin#section=2D-Structure Formula: C21H43N5O7, Molecular Weight: 477.603 g/mol CAS Number: 1403-66-3 Delivery Method: For use in treating cUTIs, gentamicin comes as a liquid to be injected intravenously or intramuscularly. Side Effects: The most frequently reported side effects associated with gentamicin injections are ototoxicity and nephrotoxicity. Other side effects of the drug include hearing loss, back pain, blurred vision, and stomach cramps. Other Names: Alternative names for gentamicin include the following: genticin, garamycin, gentacycol, and gentamicin sulfate. The IUPAC name for gentamicin is 2-[4,6-diamino-3-[3-amino-6-[1- (methylamino)ethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol. Maker or Company: The primary manufacturer of gentamicin is Valeant Pharmaceuticals International, Inc. Is it patented? Yes. Clinical Trials Information: There are 4 clinical trials involving gentamicin and cUTIs that are either complete or ongoing. Origin: Gentamicin is produced by the fermentation of Micromonospora purpurea, a type of gram-positive bacteria widely present in the environment. Alternatives to Drug: There are several alternatives to gentamicin; however, most of them are not as effective as gentamicin in treating cUTIs. The combination of ampicillin and gentamicin has proven to be a successful treatment for complicated infections. In addition, gentamicin is one of the few antibiotics for treating cUTIs that has specific drug/protein interactions. Antibiotics such as co-amoxiclav, levofloxacin, and ciprofloxacin are a few of the alternatives to gentamicin. Some of these antibiotics lack specific drug/protein interactions; instead, they typically work to disrupt bacterial cell walls. Miscellaneous: N/A Other Uses: Gentamicin injections are used to treat certain serious infections that are caused by bacteria, such as meningitis and infections of the blood, abdomen, lungs, skin, bones, joints, and urinary tract [9]. Gentamicin can also be used to treat bacterial infections of the eye and skin; however, gentamicin is not given intravenously to treat these infections. References: 1. University of Maryland Medical Center. http://umm.edu/health/medical/reports/articles/urinary-tract-infection (accessed Feb. 4, 2017).2. Urinary Tract Infections. https://www.kidney.org/sites/default/files/uti.pdf (accessed Feb. 4, 2017).3. SWAB Guidelines for Antimicrobial Therapy of Complicated Urinary Tract Infections in Adults. http://www.swab.nl/swab/cms3.nsf/uploads/41949F6BD9ED10EDC1257B7F00212560/$FILE/revised%20uti%20guideline%20FINAL%20010413.pdf (accessed Feb. 4, 2017).4. Vejborg, R. M.; Hancock, V.; Schembri, M. A.; Klemm P., Comparative Genomics of Escherichia coli Strains Causing Urinary Tract Infections. Applied and Environmental Microbiology2011, 77, (10), 3268-3278.5. Yonath, Ada., The Search and Its Outcome: High-Resolution Structures of Ribosomal Particles from Mesophilic, Thermophilic, and Halophilic Bacteria at Various Functional States. Annu Rev Biophys Biomol Struct2002, 31, (1), 257-273.6. Nobel Prizes. https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2009/advanced- chemistryprize2009.pdf (accessed Feb. 4, 2017).7. Chen, C.; Chen, Y.; Wu, P.; Chen, B., Update on new medicinal applications of gentamicin: Evidence based review. Journal of the Formosan Medical Association2014, 113, (2), 72-82.8. Clinical Trials. https://clinicaltrials.gov/ct2/results?term=gentamicin&cond=%22Urinary+Tract+Infections%22 (accessed Feb. 4, 2017).9. MedlinePlus. https://medlineplus.gov/druginfo/meds/a682275.html#why (accessed Feb. 4, 2017). External Links: http://umm.edu/health/medical/reports/articles/urinary-tract-infectionhttps://www.kidney.org/sites/default/files/uti.pdfhttp://www.swab.nl/swab/cms3.nsf/uploads/41949F6BD9ED10EDC1257B7F00212560/$FILE/revised%20uti%20guideline%20FINAL%20010413.pdfhttps://www.nobelprize.org/nobel_prizes/chemistry/laureates/2009/advanced- chemistryprize2009.pdfhttps://clinicaltrials.gov/ct2/results?term=gentamicin&cond=%22Urinary+Tract+Infections%22https://medlineplus.gov/druginfo/meds/a682275.html#whyhttp://www.biochem.umd.edu/biochem/kahn/bchm465-01/ribosome/30s.htmlhttp://www.biochem.umd.edu/biochem/kahn/bchm465-01/ribosome/30s.htmlhttps://pubchem.ncbi.nlm.nih.gov/compound/gentamicin#section=2D-Structure
Motivation and Background:
Urinary tract infections (UTIs) are a type of infection caused by bacteria that travel to the bladder through the urethra. A bladder infection is called cystitis. An infection that has spread to the kidneys and ureters is called pyelonephritis. Cystitis is considered a lower urinary tract infection, whereas pyelonephritis is an upper urinary tract infection [1]. UTIs are extremely common bacterial infections, and they can occur at any time in the life of an individual. Women are especially prone to UTIs because they have shorter urethras. It is estimated that one in every five women will have at least one UTI in her lifetime. The chances of a man getting a UTI are significantly lower [2]. In addition to there being lower and upper urinary tract infections, there are also uncomplicated and complicated infections. An uncomplicated UTI is defined as being cystitis or pyelonephritis in a woman who is not pregnant, is not immunocompromised, has no anatomical or functional abnormalities of the urogenital tract, and does not exhibit signs of tissue invasion or systemic infection. All other UTIs are considered to be complicated infections (cUTIs) [3]. Symptoms of both uncomplicated and complicated UTIs include the following: a burning sensation during urination, fever or chills, an intense and constant urge to urinate, discomfort around the kidneys, cloudy or bloody urine, and intense fatigue. Escherichia coli is associated with around 90% of all urinary tract infections, both uncomplicated and complicated [4]. E. coli CFT073 is a common strain found in many cases of uncomplicated and complicated UTIs. In order to fight complicated infections, gentamicin is often used in combination with another antibiotic. Because UTIs affect so many women and are one of the most common bacterial infections in the United States, it would be well worth the investment to fund research to find more effective preventative and treatment options for the infection.
Target Information:
A prokaryotic ribosome is a cytoplasmic particle composed of RNA and protein. Ribosomes are built of two subunits that associate for mRNA translation and protein synthesis. 30S is the smaller subunit of the 70S ribosome found in prokaryotes. It complexes with the larger 50S subunit to form the 70S prokaryotic ribosome. The RNA chain found in the 30S subunit is the 16S ribosomal RNA sequence.
Size: The 50S subunit has a molecular weight of ∼1.5 × 106 Daltons and contains two RNA chains with a total of ∼3000 nucleotides and ∼35 proteins. The 30S subunit has a molecular weight of ∼8.5 × 105 Daltons and contains one RNA chain of over 1500 nucleotides and ∼20 proteins.
Location: Because prokaryotes contain no membrane-bound organelles, ribosomal subunits are always found in the cytosol.
Function in a Normal Cell: The main function of a prokaryotic ribosome is to serve as the site of mRNA translation and protein synthesis. In a normal bacterial cell, initiation of translation, elongation, and termination occur properly and work to produce functional proteins. The initiation stage of translation brings together mRNA, an aminoacyl tRNA, and the 50S and 30S subunits. In the elongation stage of translation, amino acids are added to the previous amino acid at the C-terminus of the growing chain. The final stage of translation is termination.
Figure 1: 30S subunit without the 16S rRNA from http://www.biochem.umd.edu/biochem/kahn/bchm465-01/ribosome/30s.html
Drug Information:
Aminoglycosides primarily act by binding to the aminoacyl site of the 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation. The initial steps required for proper translation, such as the binding of mRNA and the association of the 50S ribosomal subunit, are uninterrupted, but elongation fails to occur properly due to disruption of the mechanisms for ensuring translational accuracy [6]. By interrupting elongation, aminoglycosides cause the prokaryotic cell to produce non-functional proteins. The bacterial cell will be unable to carry out necessary cellular functions if it continues to produce non-functional proteins; therefore, the cell will eventually die. Gentamicin is the most commonly used aminoglycoside for cUTIs.
Schematic Figure of Drug:
Formula: C21H43N5O7,
Molecular Weight: 477.603 g/mol
CAS Number: 1403-66-3
Delivery Method: For use in treating cUTIs, gentamicin comes as a liquid to be injected intravenously or intramuscularly.
Side Effects: The most frequently reported side effects associated with gentamicin injections are ototoxicity and nephrotoxicity. Other side effects of the drug include hearing loss, back pain, blurred vision, and stomach cramps.
Other Names: Alternative names for gentamicin include the following: genticin, garamycin, gentacycol, and gentamicin sulfate. The IUPAC name for gentamicin is 2-[4,6-diamino-3-[3-amino-6-[1- (methylamino)ethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol.
Maker or Company: The primary manufacturer of gentamicin is Valeant Pharmaceuticals International, Inc.
Is it patented? Yes.
Clinical Trials Information: There are 4 clinical trials involving gentamicin and cUTIs that are either complete or ongoing.
Origin: Gentamicin is produced by the fermentation of Micromonospora purpurea, a type of gram-positive bacteria widely present in the environment.
Alternatives to Drug: There are several alternatives to gentamicin; however, most of them are not as effective as gentamicin in treating cUTIs. The combination of ampicillin and gentamicin has proven to be a successful treatment for complicated infections. In addition, gentamicin is one of the few antibiotics for treating cUTIs that has specific drug/protein interactions. Antibiotics such as co-amoxiclav, levofloxacin, and ciprofloxacin are a few of the alternatives to gentamicin. Some of these antibiotics lack specific drug/protein interactions; instead, they typically work to disrupt bacterial cell walls.
Miscellaneous: N/A
Other Uses: Gentamicin injections are used to treat certain serious infections that are caused by bacteria, such as meningitis and infections of the blood, abdomen, lungs, skin, bones, joints, and urinary tract [9]. Gentamicin can also be used to treat bacterial infections of the eye and skin; however, gentamicin is not given intravenously to treat these infections.
References:
1. University of Maryland Medical Center. http://umm.edu/health/medical/reports/articles/urinary-tract-infection (accessed Feb. 4, 2017).2. Urinary Tract Infections. https://www.kidney.org/sites/default/files/uti.pdf (accessed Feb. 4, 2017).3. SWAB Guidelines for Antimicrobial Therapy of Complicated Urinary Tract Infections in Adults. http://www.swab.nl/swab/cms3.nsf/uploads/41949F6BD9ED10EDC1257B7F00212560/$FILE/revised%20uti%20guideline%20FINAL%20010413.pdf (accessed Feb. 4, 2017).4. Vejborg, R. M.; Hancock, V.; Schembri, M. A.; Klemm P., Comparative Genomics of Escherichia coli Strains Causing Urinary Tract Infections. Applied and Environmental Microbiology 2011, 77, (10), 3268-3278.5. Yonath, Ada., The Search and Its Outcome: High-Resolution Structures of Ribosomal Particles from Mesophilic, Thermophilic, and Halophilic Bacteria at Various Functional States. Annu Rev Biophys Biomol Struct 2002, 31, (1), 257-273.6. Nobel Prizes. https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2009/advanced- chemistryprize2009.pdf (accessed Feb. 4, 2017).7. Chen, C.; Chen, Y.; Wu, P.; Chen, B., Update on new medicinal applications of gentamicin: Evidence based review. Journal of the Formosan Medical Association 2014, 113, (2), 72-82.8. Clinical Trials. https://clinicaltrials.gov/ct2/results?term=gentamicin&cond=%22Urinary+Tract+Infections%22 (accessed Feb. 4, 2017).9. MedlinePlus. https://medlineplus.gov/druginfo/meds/a682275.html#why (accessed Feb. 4, 2017).
External Links:
http://umm.edu/health/medical/reports/articles/urinary-tract-infectionhttps://www.kidney.org/sites/default/files/uti.pdfhttp://www.swab.nl/swab/cms3.nsf/uploads/41949F6BD9ED10EDC1257B7F00212560/$FILE/revised%20uti%20guideline%20FINAL%20010413.pdfhttps://www.nobelprize.org/nobel_prizes/chemistry/laureates/2009/advanced- chemistryprize2009.pdfhttps://clinicaltrials.gov/ct2/results?term=gentamicin&cond=%22Urinary+Tract+Infections%22https://medlineplus.gov/druginfo/meds/a682275.html#whyhttp://www.biochem.umd.edu/biochem/kahn/bchm465-01/ribosome/30s.htmlhttp://www.biochem.umd.edu/biochem/kahn/bchm465-01/ribosome/30s.htmlhttps://pubchem.ncbi.nlm.nih.gov/compound/gentamicin#section=2D-Structure